BACKGROUND: In 2020, Maryland had the fourth-highest opioid overdose mortality rate in the USA. We describe substances identified in postmortem toxicology screening and designated as cause of death (COD) for overdose decedents in Maryland, including specific combinations of substances designated as COD. METHODS: We performed a retrospective analysis of N=5442 adult overdose decedents (ie, manner of death unintentional or undetermined) in Maryland between January 2020 and December 2021. Overdose mortality data from the State Unintentional Drug Overdose Reporting System. Substances were categorised into five major categories: opioids, alcohol, psychostimulants, sedative-hypnotics and psychotropic drugs. Opioids were further divided into prescription opioids (eg, oxycodone, methadone, tramadol) and illicit opioids (eg, illicitly manufactured fentanyl (IMF), heroin). RESULTS: Opioids were present in 93% of cases and designated as COD for 92%. IMF was the predominant opioid designated as COD (82% of cases), whereas heroin was COD in only 3%. Psychostimulants, predominantly cocaine, were present in 48% of cases and designated as COD in 41%. Opioids alone were COD in 39% of cases, opioids and psychostimulants in combination were COD for 27%, followed by opioids and alcohol (9%), opioids, alcohol and psychostimulants (6%), and opioids and sedative-hypnotics (4%). CONCLUSIONS: IMF is, by far, the leading cause of overdose in Maryland. For more than one-quarter of decedents, opioids and psychostimulants in combination were COD. Specific drug combinations have implications for public health surveillance and harm reduction efforts to keep people who use drugs safer from a volatile drug market and potential fatal overdose.